The possibility that long-term bisphosphonate use increases the risk of atypical femoral fractures is a growing concern in the clinical management of patients with osteoporosis. These fractures occur in the subtrochanteric or diaphyseal region of the femur with minimal trauma. While atypical femoral fractures are undoubtedly rare, their consequences are profound and life altering, making it imperative to determine whether they are linked to bisphosphonates. Our long term goal is to determine the mechanisms underlying atypical femoral fractures, in order to better identify who is at risk for these rare fractures, an improve clinical decision making regarding the initiation or interruption of bisphosphonate therapy. Currently, there is a major gap in knowledge about who may be susceptible to developing a bisphosphonate-related atypical femoral fracture. Thus, the objective of the current study is to determine whether a novel minimally invasive method for in vivo measurement of cortical bone material properties can identify those who are at risk for atypical femoral fractures Our working hypothesis is that women with atypical femoral fractures have altered cortical bone material properties that make them susceptible to this rare fracture. We further posit that these altered bone matrix properties are not clinically detectable with traditional testing methods, such as BMD, bone turnover markers or bone microarchitecture. To test this hypothesis, we propose two aims: Aim 1) Determine whether women with atypical femoral fractures have altered cortical bone tissue properties, as assessed in vivo by a new minimally invasive approach called reference point indentation; and Aim 2) Determine the predictors of cortical bone tissue properties assessed by in vivo reference point indentation. For Aim 1, we will compare cortical bone tissue properties, as assessed by novel in vivo indentation at the mid-tibia, in three groups of postmenopausal women: 1) those with recent atypical femoral fractures (n=25); 2) long term (e 5 yrs) bisphosphonate users (n=25); and 3) age-similar controls with no bisphosphonate exposure (n=50). In addition, we will assess hip and spine BMD by DXA, and volumetric density and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal tibia, as well as clinical characteristics, including vit D status, medication history, and lifestyle factors (e.g., smoking, alcohol, and physical activity). For Aim 2, will determine the association between in vivo indentation measures and hip and spine BMD, as well as volumetric bone density and microarchitecture by HR-pQCT. Successful completion of this project will address a critical gap in knowledge needed to address the pressing clinical issue of atypical femoral fractures associated with bisphosphonate use, and will also provide novel information about possible clinical utility of minimally invasive, in vivo bone indentation measurements. In line with the goals of the R21 mechanism, we will use novel technical and conceptual approaches to overcome current barriers to progress in the field. Albeit high risk, the proposed study has the potential to have a major impact on clinical management of patients with osteoporosis. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it addresses a growing concern in the clinical management of patients with osteoporosis, namely the risk of bisphosphonate-related atypical femoral fractures. While atypical femoral fractures are undoubtedly rare, their consequences are profound and life altering, making it imperative to determine who may be susceptible to these fractures. Our study addresses this issue by testing whether women with atypical femoral fractures have altered cortical bone tissue properties, as assessed by a novel, minimally invasive technique, called reference point indentation, that attempts to measure bone fragility by making a small indent in the bone surface that is about 3 to 4 times the width of a human hair.